MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain.
MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain.
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DOI：
10.1038/s41467-023-36368-5
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发表时间：
2023-02-08
影响因子：
16.6
通讯作者：
Kutateladze, Tatiana G.
中科院分区：
文献类型：
--
作者：
Becht, Dustin C.;Klein, Brianna J.;Kanai, Akinori;Jang, Suk Min;Cox, Khan L.;Zhou, Bing-Rui;Phanor, Sabrina K.;Zhang, Yi;Chen, Ruo-Wen;Ebmeier, Christopher C.;Lachance, Catherine;Galloy, Maxime;Fradet-Turcotte, Amelie;Bulyk, Martha L.;Bai, Yawen;Poirier, Michael G.;Cote, Jacques;Yokoyama, Akihiko;Kutateladze, Tatiana G.
人类乙酰转移酶MOZ和MORF与侵袭性白血病相关的染色体易位有关。致癌易位涉及MOZ/MORF的远氨基末端，其功能尚不清楚。在这里，我们确定和特点是两个结构化的翼螺旋（WH）域，WH 1和WH 2，在MORF和MOZ。WHs以合作的方式结合DNA，WH 1特异性识别未甲基化的CpG序列。结构和基因组分析表明，WHs的DNA结合功能的目标MORF/MOZ的基因启动子，刺激转录和H3 K23乙酰化，和WH 1招募致癌融合HOXA基因，触发白血病。Cryo-EM、NMR、质谱和诱变研究提供了对DNA结合机制的机械见解，其包括WH 1与含CpG的接头DNA的缔合以及WH 2与核小体的二分体的结合。MORF和MOZ中WHs及其DNA结合功能的发现可能为开发治疗与异常MOZ/MORF乙酰转移酶活性相关的疾病的疗法开辟了一条途径。人类乙酰转移酶MOZ和MORF介导发育程序，并在疾病中失调。在这里，作者鉴定了MORF/MOZ中的两个翼螺旋（WH）结构域，并表征了它们的DNA结合功能，包括WH 1对CpG的靶向作用。
Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities. Human acetyltransferases MOZ and MORF mediate development programs and are dysregulated in diseases. Here the authors identified two winged helix (WH) domains in MORF/MOZ and characterized their DNA binding functions, including targeting of CpG by WH1.
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